Fumes from the spleen

From our own correspondents

Fumes from the spleen

The mind of man has removed the stopper of the medicine bottle. The chemical genieformerly imprisoned within now stands before us. He is a spirit known to workmiracles, but also to wreak havoc ± to improve life or destroy it.1

In a 1959 lecture entitled `The Practical Uses of Theory,' Hans Jonas,2 a respected

moral philosopher, examined what he perceived to be a new relationship between

theory and practice in the modern age. Over the next quarter-century until his

death, Jonas reflected, wrote and lectured about the growing impact of technology

on the human condition, and on the need to rethink our moral obligations. He

began by looking back at traditional ethics and noted that it dealt, for the most

part, with the here and now. In the past, proper conduct was visible in everyday

life. The time-honoured maxims of ethical demeanour referred to current

behaviours: `Love thy neighbour as thyself'; `Tell the truth'; `Do unto others as

you would wish them to do unto you'; and so on. The effective range of human

action was small, Jonas observed, `the time span of foresight, goal setting, and

accountability was short, control of circumstances limited'. The long run of

consequences was left to chance, fate or providence. `The short arm of human

power', he noted, `did not call for a long arm of predictive knowledge'.

In medicine before World War II, for example, the remedial power of doctors

was very limited. Lewis Thomas3 recalled that his father, a general practitioner in

semirural Connecticut during the early part of this century, was influenced by Sir

William Osler's teaching of therapeutic nihilism. The nihilists rejected most of the

remedies in common use as more likely to do harm than good: `there are only a

small number of genuinely therapeutic drugs ± digitalis and morphine best of all'.

When the older Thomas made home visits, the only indispensable drug in his bag

was morphine; adrenaline was carried in case of anaphylactic shock, an

emergency that never turned up. In due course, insulin was added to the short list.

When Lewis Thomas entered medical school in 1933 very little had changed.

For example although there had been considerable progress in understanding the

causation of infectious diseases, the course of study was, if anything, even more

conservative than it had been 30 years earlier. Ìts purpose', Thomas recalled, `was

to teach the classification and recognition of disease entities... the treatment of

disease was the most minor part of the curriculum, almost left out altogether'. The

Paediatric and Perinatal Epidemiology 1998, 12, 122±127

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medical students came to realise that `we could do nothing to change the course

of the great majority of the diseases we were so busily analysing, that medi-

cine, for all its facËade as a learned profession, was in real life a profoundly

ignorant occupation'.

Needless to say, the revolutionary developments in medicine during and

following World War II changed everything. And the explosive increase in

technical knowledge, Jonas wrote, ìnformed by an ever-deeper penetration of

nature and propelled by the forces of the market and politics, has enhanced

human power beyond anything known or ever dreamed of before. Modern

technology has introduced actions of such novel scale, objects, and consequences

that the framework of former ethics cannot contain them'. `The duty of

knowledge', he continued, ìs now beyond anything required in the past: now

knowledge must be commensurate with the causal scale of our actions'.

Unfortunately, predictive knowledge always falls behind technical knowledge;

and `the gap between the ability to foretell and the power to act', Jonas warned,

`creates a novel moral problem'.

The search for and application of new drugs to treat cardiac arrhythmias is a

modern cautionary tale that reveals virtually all of the dangers feared by Jonas.

Thomas Moore4 has recently written a detailed and chilling account of that little-

noticed episode; he labels it Àmerica's worst drug disaster'.

The story begins in 1972, Moore reports, when a large American company

made decision to diversify and enter the lucrative field of drug manufacture. A

chemist in the company had just created a new compound modelled on the widely

used local anaesthetic drug, `procaine', and a pharmacologist suggested that the

new would-be anaesthetic (subsequently labelled `flecainide') might be useful as a

suppressant for patients with irregular heartbeats. Tests in laboratory animals

revealed that flecainide did indeed have potent antiarrhythmic properties. Now

the long hectic race to the clinic began. Similar local-anaesthetic-like drugs

(èncainide' and `tocainide') were also under development by the company's

competitors. Like flecainide, the rival compounds were categorised as Class I

antiarrhythmic drugs.

Over a 6-year period, studies of flecainide were conducted, first in normal

volunteers, and then in cardiac patients with premature ventricular contractions

(PVCs). The new agent appeared to be unusually effective in suppressing the

ventricular arrhythmias and, Moore notes, this encouraging information came at a

very propitious time. In 1978, a causal link was postulated connecting PVCs

(assumed to be signs of a heart's electrical instability) and the risk of sudden

cardiac death. Àny prophylactic program against sudden death', a leading

cardiologist declared, `must involve the use of antiarrhythmic drugs to subdue

[PVCs]'. Some cardiologists warned against treating asymptomatic patients on the

basis of this unproved suppression hypothesis (there was no concrete evidence to

support the hope that suppressing premature beats would prevent sudden death).

From our own correspondents 123

# 1998 Blackwell Science Ltd. Paediatric and Perinatal Epidemiology, 12, 122±127

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Nonetheless, the claim must have seemed reasonable to many doctors, because the

number of prescriptions written in the US for antiarrhythmic drugs grew

phenomenally to nearly 12 million in the year 1979. Encouraged by the growing

market, the company drew up a plan for the clinical development of flecainide.

Moore points to a crucial stipulation in the plan: suppression PVCs (not sudden

death) was adopted as the primary outcome to test the effectiveness of flecainide.

Much to their later regret, the American drug regulation authorities (FDA)

concurred in this pivotal decision to choose a surrogate outcome instead of

mortality as the criterion for effectiveness of all the new generation of Class I

drugs then under test.

Over the next 8 years, with increased use of flecainide and the similar drugs, it

became clear that the new agents could suppress and at other times induce lethal

cardiac arrhythmias ± the drugs were thought to be implicated in a worrisome

number of sudden deaths. But the companies and most doctors seemed convinced

that these adverse events were rare and, in any case, were outweighed by

demonstrable benefits: suppression of PVCs. After much debate and numerous

meetings within FDA and with the drug companies, approval was granted in 1986

with the requirement for a warning label calling attention to the risk of

proarrhythmic effects and `reserving treatment for patients in whom benefits

outweigh the risks'. The caution could not have been taken seriously, Moore

opined, because 2 years later pharmacists were filling 57 000 prescriptions for

flecainide every month ± a 50% increase over the previous year.

Questions about safety and effectiveness of these drugs persisted among a

sceptical minority, who complained that controlled trials (as required by

American law) had not been carried out before FDA approval. Belatedly, a 27-

centre randomised clinical trial was mounted by the US National Heart, Lung and

Blood Institutes (NHLBI)5 to test whether the suppression of ventricular

arrhythmias with flecainide, encainide or moricizine would reduce mortality

compared with controls who received a placebo. Only patients who survived a

heart attack were eligible for this Cardiac Arrhythmia Suppression Trial (CAST);

additionally, there had to be documented evidence of asymptomatic or mildly

symptomatic ventricular arrhythmias, and a demonstration that these ectopic

beats were suppressed with the drug under test before each candidate was

enrolled. (It is important to note that the design of CAST called for a one-tail test of

the pretrial hypothesis. The likelihood of lethal effects was thought to be too

remote to require the more conservative two-tail test, which would consider the

probabilities of either effectiveness or harm).

Recruitment was begun in June 1987 at centres in the US, Canada and Sweden.

In April 1989, CAST was truncated 3 years earlier than planned, when it was

found that the pretrial assumption was wrong ± two of the drugs were harmful.

Twice as many patients receiving flecainide or encainide died as compared with

controls. As Moore points out, CAST finally provided a definitive test of the

124 From our own correspondents


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relevance of the surrogate outcome. Not only did effective suppression of PVCs

fail to prevent sudden deaths, but also, with these two drugs, suppression was

associated with more fatalities than in non-suppressed controls! Patients receiving

moricizine (the least effective suppressant) or placebo experienced an insignificant

but favourable trend in mortality.

The CAST results caused considerable breast-beating in the FDA but,

surprisingly, the outcome was of only moderate interest to news media. Moore

is appalled by the failure of reporters to probe the overall dimensions of the

disaster. Approximately 200 000 patients in the US were taking flecainide and

encainide. Even under the most conservative assumptions, the estimated total

number of deaths comes to more than 5000 in 1 year. Moreover, if only the excess

deaths among patients receiving other Class I antiarrhythmic drugs during the 2-

year interval of CAST are taken into account, there must have been tens of

thousands of drug-related fatalities in the US. The number of similar deaths in

other countries has never been reckoned. The total, Moore charges, is without

precedent in modern medicine.

The NHLBI-sponsored evaluation of antiarrhythmic drugs did not end in 1989;

the original trial continued as CAST II6 with a new protocol in which only

moricizine was now compared with placebo. In 1990, while CAST II was still subjudice, moricizine was approved by the FDA, with a warning that it should be

used only for `life-threatening rhythm disturbances'. Nonetheless, the drug was

advertised in medical journals as `Now available ± effective and safe [sic]'. But the

moricizine trial, CAST II, ended like its predecessor: the second trial was

terminated early because of èxcess mortality' in the treatment arm. And the

research team concluded (with a tortured understatement): `CAST I and II

demonstrate that suppression of ventricular arrhythmias has not been linked to

improved survival'. Ìn this manner', Moore reports, `the saga of the antiar-

rhythmic drugs sputtered to a quiet and inconclusive close'. Only two newspapers

carried a brief story reporting the results of CAST II.

What went wrong with the laudable attempt to fashion logical treatment based

on a very reasonable, but untested, hypothesis? Hans Jonas might argue that the

potency of the new drugs combined with such limited predictive knowledge

created an enormous burden of responsibility. And it is the magnitude of the

stakes that leads to Jonas' pragmatic rule: `give the prophecy of doom priority

over the prophecy of bliss'. An ìmperative of responsibility' might have

persuaded the clinicians to use the most rigorous methodology (current controls)

in their earliest attempts to investigate a beneficent use of the untested drugs.

Additionally, Jonas might have counselled a very slow and cautious acceptance of

the drugs for general use. As he once warned,7 `the tempo [of progress],

compulsive as it may become, has nothing sacred about it...too ruthless a pursuit

of scientific progress would make its most dazzling triumphs not worth having'.

MALCONTENT



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References

1 Lasagna L. The diseases drugs cause. Perspectives in Biology and Medicine 1964;(Summer):457±470.2 Jonas H. The Imperative of Responsibility. In Search for an Ethics for the Technological Age(translation). Chicago: University of Chicago Press, 1984.3 Thomas L. The Youngest Science. New York: Viking, 1983.4 Moore TJ. Deadly Medicine. Why Tens of Thousands of Heart Patients Died in America'sWorst Drug Disaster. New York: Simon & Schuster, 1995.5 The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report:increased mortality due to encainide or flecainide in a randomized trial of arrythmiasuppression after myocardial infarction. New England Journal of Medicine 1989; 321:406±412.6 Cardiac Arrhythmia Suppression Trial (CAST II) Investigators. Effect of theantiarrhythmic agent moricizine on survival after myocardial infarction. New EnglandJournal of Medicine 1992; 327:227±233.7 Jonas H. Philosophical reflections on experimenting with human subjects. Daedalus1969; 219:223±245.

So What?

Numbers

I never liked arithmetic, so when given the chance at the age of 13 to give up

studying mathematics I took it, and opted to do typing and book-keeping instead.

Strange now to think that such a choice was even offered by a state grammar

school back in 1949. And how I managed to get into the London School of

Economics ± albeit as a mature student ± to take an economics degree having

dropped mathematics at 13 remains one of life's many mysteries. Equally

mysterious is how I managed to avoid any courses or exam questions that

demanded even a minimum level of numeracy.

Also remaining a mystery is anything to do with adding up or measuring.

Take measuring risk. In January this year I was one of nine first cousins. As

1997 ends, I am one of only seven first cousins. Does this mean that if we cousins

continue to die at two per year I have a maximum of 3 years and 6 months to live?

I asked a bright, numerate, younger colleague, and he said ± obviously keen to

humour the boss ± that I should think of a group I also belong to that might extend

my life. I managed to think of three: women live longer than men, the middle

classes live longer than the working classes and my father is still going

argumentatively strong at 87 (and my late lamented mother lasted until 91).

Which gives me time to consider decimalisation. How long ago is it now that

Britain adopted decimal currency and foreign ways of measuring (litres instead of

pints, centimetres instead of inches, kilos instead of pounds, etc.)? Well, the

passing years have not helped me adapt at all. I am forever boring people by

126 From our own correspondents


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telling them what this or that would have cost in the old days. I have a table

converting Centigrade to Fahrenheit sellotaped to the sideboard so that I can

decide whether it's hot or cold before I leave the house. I have a table converting

new weights to old weights in case I ever find time to cook from a new recipe book

± rather than the safe 40-year-old one I use.

Size is a problem too. And I do not mean my weight or girth problems. I

bought some plastic food containers from a lovely mail order catalogue the other

week, guessing blindly that the sizes I was ordering would be about right. Well,

they were not. Much too big, which explained why they were rather expensive,

but did not help at all with my freezer storage problems.

Like not having heard of the latest pop stars or the latest films, such old-

fashioned problems matter less and less. On the one hand, with pocket calculators

and computers who needs to add up nowadays? Such skills are only useful if one

wants to check every bill presented by newsagent, waiter or milkman. On the other

hand, aspects of one's life that were a matter of shame when one was younger start

becoming the source of affectionate amusement once one is seriously old.

Will retirement ± on the distant (very distant) horizon ± offer the time to learn

something mathematical at long last? Yes, perhaps it will, but not before reading

all those books long bought and still unread.

JEAN GAFFIN



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Fumes from the spleen